Novel FXIa inhibitor offers promising antithrombotic therapy

Abstract

MedWire News: Preclinical research has shown that a small-molecule selective inhibitor of factor (F)XIa is a promising antithrombotic therapy.

Compound BMS-262084, an irreversible factor FXia inhibitor containing 4-carboxy-2-azetidinone, has been shown to have antithrombotic efficacy when given intravenously in rat models of arterial and venous thrombosis.

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To extend these studies, Pancras Wong (Bristol-Myers Squibb, Pennington, New Jersey, USA) and associates studied the effects of intravenous BMS-262084 treatment given to rabbits 1 hour before thrombosis was induced.

As reported in the Journal of Thrombosis and Thrombolysis, BMS-262084 was associated with dose-dependent antithrombotic activity, reducing thrombus weight or increasing blood flow by 50% versus control in arteriovenous shunt models at doses of 0.4mg/kg/h.

The same 50% target was achieved in venous thrombosis models at doses of 0.7 mg/kg/h, and electrolytic-mediated carotid arterial thrombosis at doses of 1.5 mg/kg/h.

Ex vivo, BMS-262084 increased activated partial thromboplastin time (aPTT) in a dose-dependent manner, but did not alter prothrombin time or thrombin time, validating the assumption that the compound inhibits FXIa.

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Of note, the antithrombotic properties of BMS-262084 were significantly linked with the compound's ex vivo aPTT, suggesting the latter measure could be used as an accurate marker of BMS-262084 pharmacodynamics.

"This study shows that BMS-262084... is efficacious in multiple rabbit models of thrombosis at doses that preserve hemostasis," write the authors.

While advising caution in applying preclinical findings to human outcomes, the researchers conclude that their findings further support the idea that "FXIa is an attractive target in the development of anticoagulants possessing an improved therapeutic window."